Purdue University researchers are reporting demonstration of a prototype chip that allows thousands of chemical compounds to be tested simultaneously for their ability to change the operation of cell membrane pumps.

Researchers at Purdue University have built and demonstrated a prototype for a new class of miniature devices to study synthetic cell membranes in an effort to speed the discovery of new drugs for a variety of diseases, including cancer.

The researchers created a chip about one centimeter square that holds thousands of tiny vessels sitting on top of a material that contains numerous pores. This "nanoporous" material makes it possible to carry out reactions inside the vessels.

The goal is to produce "laboratories-on-a-chip" less than a half-inch square that might contain up to a million test chambers, or "reactors," each capable of screening an individual drug, said Gil Lee, the project's leader and an associate professor of chemical engineering.

"What we are reporting now is a proof of concept," said Lee, one of three researchers who wrote a paper that details new findings in the current issue (Feb. 15) of the journal Langmuir. The two other researchers are Zhigang Wang, a postdoctoral fellow at Purdue; and Richard Haasch, a research scientist at the University of Illinois at Urbana-Champaign.

The work is part of overall research being carried out by an interdisciplinary team of scientists and engineers who are members of a Center for Membrane Protein Biotechnology. The center was created at Purdue in 2003 through a grant from the Indiana 21st Century Research and Technology Fund, established by the state of Indiana to promote high-tech research and to help commercialize innovations.

The vessels discussed in the research paper are cylindrical cavities that are open at the top and sealed at the bottom with a material called alumina, which contains numerous pores measured in nanometers, or billionths of a meter.

Researchers are working to duplicate how cell membranes function on chips in order to test the potential effectiveness of new drugs to treat diseases. Membranes, which surround cells and regulate the movement of molecules into and out of the cells, contain a variety of proteins, some of which are directly responsible for cancer's ability to resist anti-tumor chemotherapy drugs. These proteins act as tiny pumps that quickly remove chemotherapy drugs from tumor cells, making the treatment less effective. Cancer cells exposed to chemotherapy drugs produce a disproportionately large number of the pumps, causing the cells to become progressively more resistant to anticancer drugs.

Engineers and scientists in the Purdue center are trying to find drugs that deactivate the pumps, which would make the chemotherapy drugs more effective. The researchers are developing synthetic cell membranes to mimic the real thing and then plan to use those membranes to create chips containing up to 1 million test chambers. Each chamber would be covered with a membrane containing the proteins, and the chambers could then be used to search for drugs that deactivate the pumps, Lee said.

Such an advanced technology could be used to quickly screen millions of untested drug compounds that exist in large pharmaceutical "libraries." The chips could dramatically increase the number of experiments that are possible with a small amount of protein.

"It's been very hard to study these proteins because they are difficult to produce in large quantities," Lee said. "The devices we have created offer the promise of making chips capable of running thousands of reactions with the same amount of protein now needed to run only about 10 reactions."

Findings being reported in the paper detail how researchers created the device with the same "microfabrication" techniques used to make computer chips. The reactors range in diameter from about 400 to 60 microns, or millionths of a meter. Human hairs are about 100 microns wide.

Note that there are two advantages to this chip. First off, more tests can be run at once in parallel. But also note that the protein used in the test is difficult to isolate or produce. The small size of each cell on the chip allows much smaller amounts of the protein to be used per test. So the protein can be used to run orders of magnitude more tests.

The ability to run orders of magnitude more tests in parallel will speed up many types of experiments. Notably, it will speed up screening for drugs to use against cancer as noted above. Cancer cells develop many mutations that give them resistance to anti-cancer chemotherapies and other anti-cancer agents. Once the tools area developed to very rapidly test resistant cancers against drugs that might block their mechanisms of resistance the possibility opens up that anti-cancer drugs might be able to be developed so quickly that once drug-resistant cancer cells emerge drugs that block the mechanisms of resistance could be found before patients would otherwise be expected to die.

In a recent report on how lung cancer becomes resistant to the anti-cancer drug gefitinib (Iressa) scientists guessed that the mechanism of resistance had to do with a mutation in epidermal growth factor protein (EGFR) which is where gefitinib binds to stop cancer growth. These scientists at Harvard's Beth Israel Deaconess Medical Center (BIDMC) sequenced the EGFR gene in a patient with gefitinib-resistant cancer and sure enough their hunch was right. Well, people are dying from their gefitinib-resistant cancers and other cancer drug resistant cancers. What we need are DNA sequencing technologies and other technologies for testing cancer cells and screening drug candidates that are extremely fast. then once a drug-resistant mutation shows up in a patient the identification of the mechanism of drug resistance and the search for a new drug will be able to be done before the patient dies.

Once we have biochips and nanotechnology that are fast enough to adapt to the cancers faster than the cancers can adapt to each new round of drug treatment then it will be possible to cure cancer. The shift toward the use of technologies from the semiconductor industry to do testing and manipulation of biological systems is going to lead to orders of magnitude faster and cheaper ways to develop drugs and other disease treatments.